Hypoglycemia in type 1 diabetes

ISRCTN	ISRCTN74214605
DOI	https://doi.org/10.1186/ISRCTN74214605
ClinicalTrials.gov number	NCT06325202
Secondary identifying numbers	STUDY00020946

Submission date: 11/03/2024
Registration date: 26/03/2024
Last edited: 03/04/2025

Recruitment status: Recruiting
Overall study status: Ongoing
Condition category: Nutritional, Metabolic, Endocrine

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
People with type 1 diabetes (T1D) are at risk of complications that can be minimized by maintaining normal blood glucose levels. Of particular concern to people with T1D is hypoglycemia, in which blood glucose levels drop below normal and can lead to sweating, confusion, excessive hunger and in some cases, coma. On average, a person with T1D has two episodes of hypoglycemia per week and one or more episodes per year of severe hypoglycemia, defined as requiring third-party assistance. In addition, a person who has experienced repeated hypoglycemic events over the years is at risk of becoming less aware of the oncoming symptoms, which places the person at greater risk. This phenomenon is called impaired awareness of hypoglycemia (IAH) and affects 20-25% of individuals with T1D. Therefore, this study aims to compare hybrid closed loop (HCL) devices with psycho-educational programs to determine which can reduce the occurrence of IAH events. An HCL system, also known as an artificial pancreas, consists of a continuous glucose monitor (CGM), an insulin pump, and an algorithm that automatically manages insulin delivery.

Who can participate?
Patients aged 18-75 years who have been clinically diagnosed with T1D for at least 10 years and have experienced impaired awareness of hypoglycemic events

What does the study involve?
A participant will be assigned to an intervention that consists of an HCL device and/or a psycho-educational program. After 12 months on the intervention, the investigators will determine whether the intervention has been effective in reducing the occurrence of IAH events. If yes, then the participant will continue with that intervention for months 13-24. If no, then the participant will be assigned an alternative intervention for months 13-24. Thus, a participant will be asked to continue in the study for 24 months, during which time there will be nine in-person clinic visits and 11 telephone/videoconference contacts.

What are the possible benefits and risks of participating?
The potential benefits of the CLEAR trial are that participants can learn the approach that works best for them in identifying and responding to hypoglycemic events. The risks from study participation include potential skin reactions where the continuous glucose monitor needle is inserted, potential bruising from blood draws (venipuncture), and the potential for hypoglycemic and hyperglycemic events.

Where is the study run from?
The Coordinating Center for the CLEAR trial is located at the Penn State College of Medicine (USA), and the eight recruitment sites are located at:
1. Advent Health (USA)
2. University of California, San Diego (USA)
3. University of Kentucky (USA)
4. University of Minnesota (USA)
5. University of Pennsylvania (USA)
6. University of Leicester (UK)
7. University of Sheffield (UK)
8. University of Melbourne (Australia)

When is the study starting and how long is it expected to run for?
September 2022 to December 2027

Who is funding the study?
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (USA)

Who is the main contact?
1. Vernon M. Chinchilli, vchinchi@psu.edu
2. Abid Kazi, akazi@pennstatehealth.psu.edu
3. Venus Grella, vgrella@pennstatehealth.psu.edu

Contact information

Dr Elizabeth Seaquist
Principal Investigator

University of Minnesota
Medical School
MMC 194 Mayo
420 Delaware St. SE
Minneapolis, MN
55455
United States of America

Phone	+1 (0)612 625 3654
Email	seaqu001@umn.edu

Dr Simon Heller
Principal Investigator

School of Medicine and Biosciences
University of Sheffield
Beech Hill Road
Room FU24
Sheffield
S10 2RX
United Kingdom

Phone	+44 (0)114 215 9009
Email	s.heller@sheffield.ac.uk

Dr Vernon Chinchilli
Principal Investigator

Department of Public Health Sciences
Penn State College of Medicine
90 Hope Drive, Suite 2200
Hershey, PA
17033
United States of America

ORCID ID	0000-0001-6488-7809
Phone	+1 (0)717 531 7178
Email	vchinchi@psu.edu

Ms Venus Grella
Scientific

Department of Public Health Sciences
Penn State College of Medicine
90 Hope Drive, Suite 2200
Hershey, PA
17033
United States of America

Phone	+1 (0)717 531 0003, Ext 343413
Email	vgrella@pennstatehealth.psu.edu

Dr Abid Kazi
Public

Department of Public Health Sciences
Penn State College of Medicine
90 Hope Drive, Suite 2200
Hershey, PA
17033
United States of America

Phone	+1 (0)717 531 0003, Ext 320036
Email	akazi@pennstatehealth.psu.edu

Study information

Study design	Multicenter unblinded sequential multiple assignment randomized trial (SMART) design over 24 months with possible re-randomization at 12 months
Primary study design	Interventional
Secondary study design	Sequential Multiple Assignment Randomized Trial (SMART) design
Study setting(s)	University/medical school/dental school
Study type	Treatment
Scientific title	Closed loop and education for hypoglycemia awareness restoration (CLEAR)
Study acronym	CLEAR
Study objectives	Hypothesis 1: At 12 months, those allocated to Usual Care plus My HypoCOMPaSS will be more likely to have improved counter-regulatory responses (CRR) and total symptomatic responses than those allocated to hybrid closed loop (HCL). Hypothesis 2: At 12 months, those allocated to HCL plus My HypoCOMPaSS will be more likely to have improved hypoglycemic awareness and improved CRR than those using HCL alone. Hypothesis 3: At 24 months, CRR will improve further among those who had restored CRR at 12 months. Hypothesis 4: At 24 months, those allocated to HARPdoc for months 12-24 will be more likely to have improved hypoglycemic awareness and CRR than those who continue with the therapy allocated at baseline.
Ethics approval(s)	1. Approved 31/10/2024, Penn State Human Research Protection Program (101 Technology Center, University Park, PA, 16802, United States of America; +1 (0)814 865 1775; irb-orp@psu.edu), ref: STUDY00020946 2. Approved 28/08/2024, East Midlands - Leicester Central Research Ethics Committee (2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 207 104 8284; leicestercentral.rec@hra.nhs.uk), ref: 24/EM/0156
Health condition(s) or problem(s) studied	Type 1 diabetes with impaired awareness of hypoglycemia
Intervention	The CLEAR trial involves three interventions in various combinations: 1. Hybrid closed loop (HCL) systems consist of a continuous glucose monitor (CGM), an insulin pump, and an algorithm that automatically modulates insulin delivery based on CGM sensor interstitial glucose values. HCL systems thus increase insulin delivery when the sensor glucose is predicted to be high and decrease insulin delivery when the sensor glucose is predicted to be low, and so are designed to help maintain time in range. 2. My HypoCOMPaSS (MyHC) is a brief, standardized psycho-educational program delivered in small groups. Facilitated discussions focus on advocating rigorous avoidance of hypoglycemia while maintaining time in target glycemic range. The four compass points (NESW) are used to illustrate the imperatives: ‘Now; No delay’ (never delay hypoglycemia treatment); ‘Establish your Extra risks’ (and times when risk is highest); ‘Scan for Subtle Symptoms’ (of hypoglycemia); be Wary even While asleep (through watchful detection and active prevention of hypoglycemia while asleep). 3. The HARPdoc intervention is a psychological intervention, delivered to small groups of adults with type 1 diabetes (n = approx. 6) by two diabetes educators trained and supported by a clinical psychologist, which uniquely addresses the unhelpful health beliefs of people with treatment-resistant impaired awareness of hypoglycemia and severe hypoglycemia. The educators use motivational interviewing and cognitive behavioral theory to address the main cognitive barriers to hypoglycemia avoidance addressed above. CLEAR invokes a sequential multiple assignment randomized trial (SMART) design, which is an adaptive design. Participants not responding well to their initially randomized treatment are assigned/randomized to alternative treatments. There are two strata of study participants in the CLEAR trial, those naïve to an HCL device and those not naïve to an HCL device. HCL naïve stratum: 1. Participants randomized to the HCL device who show improvement of the counterregulatory epinephrine and autonomic symptom responses, as determined by the measurements at 12 months, will continue with the HCL device for months 12-24 2. Participants randomized to the HCL device who do not show improved epinephrine and autonomic symptom responses, as determined by the measurements at 12 months, will be re-randomized to continued HCL (to determine if more time is needed for the intervention to be effective) or HCL + HARPdoc for months 12-24 3. Participants randomized to usual care (UC) + MyHC who show improved epinephrine and autonomic symptom responses as determined by the measurements at 12 months, will continue with UC + MyHC for months 12-24 to determine the durability of improved epinephrine and autonomic symptom responses 4. Participants randomized to UC + MyHC who do not show restoration of the counterregulatory epinephrine and autonomic symptom responses as determined by the measurements at 12 months, will be assigned to HCL for months 12-24 HCL non-naïve stratum: 1. Participants randomized to the HCL device who show improvement of the counterregulatory epinephrine and autonomic symptom responses, as determined by the measurements at 12 months, will continue with the HCL device for months 12-24 2. Participants randomized to the HCL device who do not show improvement of the counterregulatory epinephrine and autonomic symptom responses, as determined by the measurements at 12 months, will be re-randomized to HCL alone (to determine if more time is needed for the intervention to be effective) or to HCL + HARPdoc, an IAH psychoeducational program, for months 12-24 3. Participants randomized to HCL + MyHC who show improvement of the counterregulatory epinephrine and autonomic symptom responses, as determined by the measurements at 12 months, will continue with HCL + MyHC for months 12-24 4. Participants randomized to HCL + MyHC who do not show improvement of the counterregulatory epinephrine and autonomic symptom responses, as determined by the measurements at 12 months, will be re-randomized to continued HCL + MyHC (to determine if more time is needed for the intervention to be effective) or HCL + HARPdoc for months 12-24 The Coordinating Center will randomly assign participants to their interventions via its web-based data management system (DMS). Randomization will be stratified according to clinical center and duration of type 1 diabetes (< 25 years and ≥ 25 years). After a research coordinator confirms that a participant at day 0 is eligible for enrollment, the participant completes the baseline hyperinsulinemic-hypoglycemic clamp. Next, the research coordinator will enter the private and secure DMS via the internet and enter the appropriate information. The research coordinator will then receive the intervention assignment that the participant will follow for the first 12 months. After the 12-month visit with the second clamp, and after the lab analysis of epinephrine is determined, the research coordinator again will enter the DMS and enter the appropriate information and receive instructions as to whether the participant will maintain the current intervention or be re-randomized to a new intervention. Study interventions will not be blinded.
Intervention type	Mixed
Primary outcome measure	1. Epinephrine (pg/ml) measured using a plasma sample - a change in epinephrine (pg/ml) that exceeds 125 pg/ml between (1) 12 months and baseline, and (2) 24 months and baseline, measured during the clamp studies at 0 (baseline), 12, and 24 months 2. Hypoglycemia symptoms measured using the Towler questionnaire - the Towler questionnaire consists of 12 questions each on a 0-6 Likert scale; a change in the questionnaire that exceeds 20% between (1) 12 months and baseline, and (2) 24 months and baseline, measured during the clamp studies at 0 (baseline), 12, and 24 months
Secondary outcome measures	1. Glucagon measured from a plasma sample during the clamp studies at 0 (baseline), 12, and 24 months 2. Pancreatic polypeptide measured from a plasma sample during the clamp studies at 0 (baseline), 12, and 24 months 3. Free fatty acids measured from a plasma sample during the clamp studies at 0 (baseline), 12, and 24 months 4. Glucose infusion rate, measured as the rate at which dextrose is administered, during the clamp studies at 0 (baseline), 12, and 24 months 5. HbA1c measured from a plasma sample during the clamp studies at 0 (baseline), 12, and 24 months 6. % of time with hypoglycemia <70 mg/dL determined from the continuous glucose monitor (CGM) sensor, measured during the 4 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 7. % of time with hypoglycemia <54 mg/dL determined from the continuous glucose monitor (CGM) sensor, measured during the 4 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 8. Number of hypoglycemic events determined from the continuous glucose monitor (CGM) sensor, measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months 9. % time with glucose in range determined from the continuous glucose monitor (CGM) sensor, measured during the 4 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 10. Sensor glucose coefficient of variation determined from the continuous glucose monitor (CGM) sensor, measured during the 4 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 11. Sensor use as the average number of days per week determined from the continuous glucose monitor (CGM) sensor, measured during the 4 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 12. Glycemia risk index determined from the continuous glucose monitor (CGM) sensor, measured during the 4 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 13. Trail Making Test Part B – the amount of time required to complete the test during the clamp studies at 0 (baseline), 12, and 24 months 14. Four Choice Reaction Time, which measures reaction time and coordination, during the clamp studies at 0 (baseline), 12, and 24 months 15. Sleep duration determined from an activity monitor smartwatch, measured during the 2 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 16. Sleep quality determined from an activity monitor smartwatch, measured during the 2 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 17. 24-hour step count determined from an activity monitor smartwatch, measured during the 2 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 18. Exercise bouts determined from an activity monitor smartwatch, measured during the 2 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 19. Resting heart rate determined from an activity monitor smartwatch, measured during the 2 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 10. Heart rate during exercise determined from an activity monitor smartwatch, measured during the 2 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 11. Heart rate variability determined from an activity monitor smartwatch, measured during the 2 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 12. Sleep quality, hypoglycemia fear, hypoglycemia burden, and other symptoms measured using the Hypo-METRICS questionnaire, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia, measured 2 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 13. Confidence in staying safe from severe hypoglycemic events measured using the Hypoglycemic Confidence Scale questionnaire, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia, measured 2 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 14. Activities to avoid hypoglycemia and fears about hypoglycemia measured using the Hypoglycemia Fear Survey-II, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia, measured 2 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 15. Attitudes to, and activities to avoid, hypoglycemic events measured using the Attitudes to Awareness of Hypoglycaemia, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia, measured 2 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 16. Distress encountered in daily living due to type 1 diabetes measured using the Type 1 Diabetes Distress Scale, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia, measured 2 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 17. Activities pursued for managing one’s diabetes measured using the Diabetes Self-Management Questionnaire, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia, measured 2 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 18. Activities pursued to manage one’s diabetes measured using the Diabetes Management Experiences Questionnaire, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia, measured 2 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 19. Sleep quality and sleep disturbance measured using the PROMIS Sleep Disturbance – Short Form 8a, measured 2 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 20. Anxiety and depression measured using the Hospital Anxiety and Depression Scale, measured 2 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 21. Experiences and worries about hypoglycemic events measured using the 12-Item Hypoglycemia Impact Profile, measured 2 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 22. Quality of life measured using EQ-5D-5L 2 weeks prior to each clamp study at 0 (baseline), 12, and 24 months 23. Device-related adverse events recorded using a self-reported data collection form throughout the duration of the 24 months of follow-up 24. Severe hypoglycemic events recorded using a self-reported data collection form throughout the duration of the 24 months of follow-up 25. Diabetic ketoacidosis (DKA) events recorded using a data collection form completed by a research coordinator throughout the duration of the 24 months of follow-up 26. Hospitalizations recorded using a data collection form completed by a research coordinator throughout the duration of the 24 months of follow-up 27. Emergency room (ER) visits recorded using a data collection form completed by a research coordinator throughout the duration of the 24 months of follow-up 28. Major adverse cardiovascular events (MACE) recorded using a data collection form completed by a research coordinator throughout the duration of the 24 months of follow-up 29. All-cause mortality recorded using a data collection form completed by a research coordinator throughout the duration of the 24 months of follow-up
Overall study start date	23/09/2022
Completion date	31/12/2027

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Upper age limit	75 Years
Sex	Both
Target number of participants	324
Key inclusion criteria	1. Age 18-75 years 2. Clinical diagnosis of type 1 diabetes 3. Gold Score or Clarke Score ≥4 (highly associated with IAH) 4. Random non-fasting C-peptide <200 pmol/L 5. Diabetes duration ≥10 years 6. HbA1c <10.5% 7. Total Daily Insulin Dose of <1 unit/kg 8. Ability to read and speak English (because validated non-English versions of the cognitive tests and the educational interventions are not available)
Key exclusion criteria	1. Medical conditions that limit participation in study activities, as determined by the PI (including but not limited to cognitive dysfunction, reduced hearing, reduced vision, cancer under active treatment, untreated angina, and organ failure) 2. Active alcohol or drug abuse, as defined by DSM criteria of either 2.1. Recurrent use of alcohol/drugs resulting in a failure to fulfil major role obligations at work, school, or home 2.2. Recurrent alcohol/drug use in situations in which it is physically hazardous, or 2.3. Recurrent alcohol or drug-related legal problems 4. Social determinants of health that limit participation in study activities, as determined by the PI (including but not limited to homelessness, food insecurity, and inadequate social support) 5. Seizure disorder unrelated to hypoglycemia-associated seizures, unless documented seizure-free for >12 months and on a stable regimen of anticonvulsant therapy 6. Skin conditions that would preclude the use of a CGM 7. Super-physiologic exposure to steroids within one month of enrollment 8. eGFR <45 ml/min/1.73 m2 9. History of bariatric surgery that irreversibly alters gut innervation and structure 10. Hyper- or hypokalemia (serum potassium >5.5 or <3.5 mmol/L)* 11. Hemoglobin <10 g/dL* 12. Medical condition that requires intermittent or continuous use of glucocorticoids at greater than physiological replacement doses 13. Pregnancy, plan for pregnancy, or breastfeeding 14. Abnormal thyroid function tests of clinical significance, as determined by PI* 15. Liver transaminases >3 times the upper limit of normal* 16. Hospitalization for mental illness in the last year 17. History of adrenalectomy * At the discretion of the PI, laboratory tests may be repeated once. If the participant is not eligible after the second attempt, then the participant may be screened again.
Date of first enrolment	27/05/2025
Date of final enrolment	30/06/2027

Locations

Countries of recruitment

Australia
England
United Kingdom
United States of America

Study participating centres

University of California, San Diego

Altman Clinical and Translational Research Institute (ACTRI)
9452 Medical Center Dr. L1W-515
La Jolla, CA
92037
United States of America

AdventHealth

Research Institute
301 East Princeton St.
Orlando, Florida
32804
United States of America

University of Kentucky

Healthy Kentucky Research Building, Room 233
760 Press Ave.
Lexington, Kentucky
40508
United States of America

University of Minnesota

Medical School
MMC 194 Mayo
420 Delaware St. SE
Minneapolis, MN
55455
United States of America

University of Pennslyvania

Perelman School of Medicine
12-134 Smilow Center for Translational Research
3400 Civic Center Blvd.
Philadelphia
19104
United States of America

University of Leicester

Diabetes Research Centre
Leicester General Hospital
Gwendolen Rd.
Leicester
LE5 4PW
United Kingdom

University of Sheffield

School of Medicine and Biosciences
Beech Hill Road
Room FU24
Sheffield
S10 2RX
United Kingdom

University of Melbourne

St Vincent’s Hospital
35 Victoria Pde.
Fitzroy, Victoria
3065
Australia

Sponsor information

National Institute of Diabetes and Digestive and Kidney Diseases
Government

Division of Diabetes, Endocrinology, & Metabolic Diseases
6707 Democracy Blvd
Bethesda, MD
20892
United States of America

Phone	+1 (0)301 594 4724
Email	ga96b@nih.gov
Website	http://www.niddk.nih.gov/
"ROR"	https://ror.org/00adh9b73

Funders

Funder type

Government

National Institute of Diabetes and Digestive and Kidney Diseases
Government organisation / National government

Alternative name(s): NIH National Institute of Diabetes and Digestive and Kidney Diseases, NIH/National Institute of Diabetes, Digestive & Kidney Diseases, Experimental Biology and Medicine Institute, National Institute of Arthritis and Metabolic Diseases; National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases, NIDDK, NIAMDD
Location: United States of America

Results and Publications

Intention to publish date	31/12/2027
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Stored in publicly available repository, Available on request
Publication and dissemination plan	The researchers plan to publish the primary results of the CLEAR trial in a high-impact diabetes journal.
IPD sharing plan	The datasets generated during and/or analyzed during the CLEAR trial will be stored in a publicly available repository: NIDDK Central Repository (https://repository.niddk.nih.gov/home/). It is anticipated that the datasets will be available at the NIDDK Central Repository during the latter part of 2028. The NIDDK Central Repository typically requires that the datasets be in SAS format and that the submission also should include a data dictionary, the data collection forms, the protocol, and the informed consent. Finally, the NIDDK Central Repository requires that the data be de-identified.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol file		06/03/2024	22/03/2024	No	No

Additional files

45163_PROTOCOL_06Mar24.pdf

Editorial Notes

03/04/2025: The following changes were made to the trial record:
1. ClinicalTrials.gov number added.
2. The recruitment start date was changed from 14/04/2025 to 27/05/2025.
20/01/2025: The recruitment start date was changed from 01/01/2025 to 14/04/2025.
18/11/2024: The ethics approval (2) was added.
04/11/2024: The ethics approval was added.
08/10/2024: The recruitment start date was changed from 01/10/2024 to 01/01/2025.
05/06/2024: The recruitment start date was changed from 01/07/2024 to 01/10/2024.
22/03/2024: Study's existence confirmed by the National Institute of Diabetes and Digestive and Kidney Diseases.